The ubiquitin/proteasome system-dependent control of mitochondrial steps in apoptosis.
ABSTRACT Insights into the role of ubiquitin-dependent signaling in the regulation of apoptosis have provided one of the most significant breakthroughs in recent years for cell death research. It has been revealed that all steps in the apoptotic cascade, including transcriptional regulation of apoptotic gene expression, outer mitochondrial membrane permeabilization and caspase activation, are under the control of the ubiquitin/proteasome system. This makes ubiquitin signaling one on the most critical life and death decision checkpoints in mammalian cells. Here we discuss the ubiquitylation-dependent regulation of the mitochondrial steps in apoptosis, with a focus on the role of regulated protein degradation in this process. The newly identified ubiquitylation-dependent processes in the Bcl-2 family-regulated outer mitochondrial membrane permeabilization, as well as the role of mitochondria-associated ubiquitin ligases and other molecular components of the ubiquitin/proteasome system in the control of mitochondrial steps in apoptosis, are discussed.
- SourceAvailable from: Luis Felipe Jave Suarez[show abstract] [hide abstract]
ABSTRACT: BACKGROUND: In Oncology, the resistance of the cancerous cells to chemotherapy continues to be the principal limitation. The nuclear factor-kappa B (NF-kappaB) transcription factor plays an important role in tumor escape and resistance to chemotherapy and this factor regulates several pathways that promote tumor survival including some antiapoptotic proteins such as Bcl-2 and Bcl-XL. In this study, we investigated, in U937 human leukemia cells, the effects of Pentoxifylline (PTX) and the MG132 proteasome inhibitor, drugs that can disrupt the NF-kappaB pathway. For this, we evaluated viability, apoptosis, cell cycle, caspases-3, -8, -9, cytochrome c release, mitochondrial membrane potential loss, p65 phosphorylation, and the modification in the expression of pro- and antiapoptotic genes, and the Bcl-2 and Bcl-XL antiapoptotic proteins. RESULTS: The two drugs affect the viability of the leukemia cells in a time-dependent manner. The greatest percentage of apoptosis was obtained with a combination of the drugs; likewise, PTX and MG132 induce G1 phase cell cycle arrest and cleavage of caspases -3,-8, -9 and cytochrome c release and mitochondrial membrane potential loss in U937 human leukemia cells. In these cells, PTX and the MG132 proteasome inhibitor decrease p65 (NF-kappaB subunit) phosphorylation and the antiapoptotic proteins Bcl-2 and Bcl-XL. We also observed, with a combination of these drugs overexpression of a group of the proapoptotic genes BAX, DIABLO, and FAS while the genes BCL-XL, MCL-1, Survivin, IkappaB, and P65 were downregulated. CONCLUSIONS: The two drugs used induce apoptosis per se, this cytotoxicity was greater with combination of both drugs. These observations are related with the caspases -9, -3 cleavage and G1 phase cell cycle arrest, and a decrease in p65 phosphorylation and Bcl-2 and Bcl-XL proteins. As well as this combination of drugs promotes the upregulation of the proapoptotic genes and downregulation of antiapoptotic genes. These observations strongly confirm antileukemic potential.Journal of Biomedical Science 02/2013; 20(1):13. · 2.46 Impact Factor